Cellular Mechanotransduction in the Pathogenesis and Treatment of CardiacFibrosis

Cardiac Fibroblast Mechanotransduction;Biomedical Engineering;Engineering;Biomedical Engineering

Galie, Peter AdamWestfall, Margaret V. ;

University of Michigan

关键词: Cardiac Fibroblast Mechanotransduction;    Biomedical Engineering;    Engineering;    Biomedical Engineering;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/89758/pgalie_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Cardiac fibrosis occurs after myocardial infarction, and contributes to both systolic and diastolic heart failure. Activation of cardiac fibroblasts to a myofibroblast phenotype is essential for fibrotic scar development. The present dissertation focuses on this phenotypic transition, specifically on the effects of mechanical stress and interactions with mesenchymal stem cells (MSC). The experimental platform used was a flexible 3D culture well that allowed simultaneous application of fluid flow and cyclic strain to collagen type I hydrogels seeded with primary rat neonatal cardiac fibroblasts. The results indicated that fibroblasts transitioned to myofibroblasts in static culture in the absence of exogenous biochemical or mechanical stimulation. Interstitial fluid flow significantly stimulated the myofibroblast transition, while cyclic strain had an opposing effect. Using chemical antagonists and lentivirally-delivered shRNA, it was found that the acute response to flow was mediated by angiotensin II receptor type I (AT1R) and transforming growth factor β (TGF-β). Cyclic strain also influenced the TGF-β pathway by attenuating the phosphorylation of smad2, a downstream effector of this signaling pathway. The experimental results were augmented with a poroelastic model of flow and gel displacement within the collagen hydrogels, which indicated that cyclic strain produced substantial interstitial fluid flow in the absence of applied cross flow. The results of the analytical model, combined with the experimental findings, suggested that cyclic strain decreased fibroblast activation even in the presence of interstitial flow. Finally, GFP-labeled MSC were injected into the cell-seeded collagen hydrogels to examine their effect on the cardiac fibroblast response. The presence of MSC significantly attenuated cardiac fibroblast activation under both static conditions and during biochemical and mechanical stimulation. Hypoxia, not mechanical stress, induced the highest levels of MSC migration, as well as the highest release of the paracrine factor, VEGF. The data suggest that AT1R can be targeted to prevent the myofibroblast transition, due to its role in fluid shear-induced fibroblast activation. Additionally, the observed beneficial effects of cyclic strain may have implications for therapies that unload the myocardium, including the use of ventricular assist devices (VADs). Finally, the effects of MSC on fibroblast activation may illuminate the mechanisms of MSC-based therapies.